Hair follicles undergo continuous cycling of controlled breakdown and re-growth in a process that is reminiscent of other oscillary processes such as the cell cycle and circadian rhythm. After the initial morphogenesis, the lower two-thirds of the hair follicle are removed by apoptosis and infiltration of immune cells in a phase referred to as catagen. Subsequently, the shortened follicles are relatively quiescent during a phase referred to as telogen. This is followed by activation and growth of the follicle in a phase referred to as anagen. While significant advances have been made in our understanding of the regulation of hair follicle morphogenesis, less is known about possible clock mechanisms that might regulate the periodic features of hair growth. The long term goal of our work is to understand the control of hair follicle cycling. To address this problem, we have taken a genomics approach wherein we have profiled global gene expression in skin during progression of three distinct hair growth cycles. New computational algorithms were then developed to identify genes that are regulated in relation to hair follicle cycling. One of our findings is that clock regulated genes, best known for their role in circadian rhythm, show a striking hair cycle-related regulation, suggesting possible role for classical clock mechanisms in hair cycling. Consistent with this model, we found that mice mutated for the central clock genes Clock and Bmal1 exhibit delayed onset of synchronized anagen. This effect of clock genes appears to be specific to timing of hair follicle growth because no morphological abnormalities are observed in hair follicles. Based on these findings, we hypothesize that clock genes play a timing role in hair cycle control. Specifically, we propose that clock factors regulate the initiation of anagen through the control of the cell cycle in hair follicle keratinocytes. To test this hypothesis, we plan first to determine the location of clock mechanisms responsible for normal timing of anagen initiation. We will analyze the hair cycle in mice with central deletion of the Bmal1 gene and skin compartment-specific knockouts of clock genes. In the second part of the proposal, we plan to start defining the pathway by which Clock and Bmal1 regulate normal timing of anagen initiation. We will use a combination of mouse models and in vitro mechanistic studies to discover the molecular mechanisms underlying the clock regulation of hair cycling. This work, which links circadian clock components to a different cyclic process, is novel and has general relevance to clock mechanisms. Specifically, the hair growth cycle is affected in many hair loss diseases, and in unwanted hair growth. The work has also relevance to activation of stem and progenitor cells in relation to regenerative medicine. In addition, deregulation of hair follicle growth mechanisms is thought to underlie many skin cancers. PUBLIC HEALTH RELEVANCE: Except for rare hair diseases associated with mutations in genes encoding structural components of the hair or structural damage of hair follicles due to inflammation, most hair loss diseases and unwanted hair growth are linked to hair cycling abnormalities. Disrupted control of hair growth is also associated with skin cancer. The proposed work, which aims to reveal new insights into growth control in hair follicles, has relevance to the control of stem and progenitor cells and is therefore highly relevant to regenerative medicine and public health in general.